Journal
BLOOD
Volume 125, Issue 2, Pages 346-357Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-06-581082
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Funding
- National Cancer Institute K99/R00 Pathway to Independence Award [CA151683]
- NIH Institute of General Medical Sciences [R01GM103893]
- US Department of Defense [CA130247]
- University Cancer Research Fund of North Carolina State
- Canada Foundation for Innovation [CA130247]
- Eli Lilly Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Novartis Research Foundation
- Pfizer
- AbbVie
- Takeda
- Janssen
- Boehringer Ingelheim
- Wellcome Trust
- Gabrielle's Angel Foundation
- Concern Foundation of Cancer Research
- American Association for Cancer Research-Debbie's Dream Foundation
- Department of Defense
- American Chemical Society Medicinal Chemistry Division
- National Institutes of Health (NIH)
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Enhancer of zestehomolog 2 (EZH2) and related EZH1 control gene expression and promote tumorigenesis via methylating histone H3 at lysine 27 (H3K27). These methyltransferases are ideal therapeutic targets due to their frequent hyperactive mutations and overexpression found in cancer, including hematopoietic malignancies. Here, we characterized a set of small molecules that allow pharmacologic manipulation of EZH2 and EZH1, which include UNC1999, a selective inhibitor of both enzymes, and UNC2400, an inactive analog compound useful for assessment of off-target effect. UNC1999 suppresses global H3K27 trimethylation/dimethylation (H3K27me3/2) and inhibits growth of mixed lineage leukemia (MLL) rearranged leukemia cells. UNC1999-induced transcriptome alterations overlap those following knockdown of embryonic ectoderm development, a common cofactor of EZH2 and EZH1, demonstrating UNC1999's on-target inhibition. Mechanistically, UNC1999 preferentially affects distal regulatory elements such as enhancers, leading to derepression of polycomb targets including Cdkn2a. Gene derepression correlates with a decrease in H3K27me3 and concurrent gain in H3K27 acetylation. UNC2400 does not induce such effects. Oral administration of UNC1999 prolongs survival of a well-defined murine leukemia model bearing MLLAF9. Collectively, our study provides the detailed profiling for a set of chemicals to manipulate EZH2 and EZH1 and establishes specific enzymatic inhibition of polycomb repressive complex 2 (PRC2) EZH2 and PRC2-EZH1 by small-molecule compounds as a novel therapeutics for MLL-rearranged
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